Many inflammatory skin disorders often result in unsightly and painful rashes, acne, persistent red veins, and acne-like skin eruptions, such as macules, nodules, and pustules that may ooze or crust. For example, rosacea, generally involves the cheeks, nose, chin, and forehead and the typical age of onset is 30 to 60 years. See e.g., Zuber T. J., Rosacea: Beyond First Blush 32 H OSP. P RACT. 188-189 (1997); THE MERCK MANUAL 813-814 (Keryn A. G. Lane et al. eds. 17th ed. 2001). Many people with rosacea incorrectly assume that they suffer from adult acne, sun or windburn, or the normal effects of aging. The symptoms of rosacea include frequent blushing and frequent irritation of the facial skin and increasingly severe erythema (abnormal redness of the skin) and telangiectasia (visible red lines due to abnormal dilatation of capillary vessels and arterioles). Pimple-like eruptions, which may be solid (called papules or nodules) or puss filled (known as pustules), may develop. Such eruptions often look like acne, but whiteheads or blackheads (open and closed comedones, respectively) are not normally present. More severe symptoms of rosacea include that characterized by rhinophyma (thickened, lobulated overgrowth of the sebaceous glands and epithelial connective tissue of the nose). If left untreated, rosacea can progress to irreversible disfigurement. Rosacea symptoms are often aggravated by sun exposure, changes or extremes in temperature, wind, and consumption of certain foods, such as spicy foods, caffeine, and alcohol.
There is no known cure for many inflammatory skin disorders, including inflammatory dermatologic disorders of the face, such as rosacea. Current treatments, which are directed to control redness, inflammation, and skin eruptions, are of limited effectiveness in many patients and, generally, can be used only for a limited duration. Standard treatments include avoidance of triggers such as sun exposure, wind exposure, alcohol consumption, spicy foods, and irritating facial cleansers, lotions, and cosmetics. Antibiotics are the traditional first line of therapy. Long-term treatment (5 to 8 weeks or more) with oral antibiotics such as tetracycline, minocycline, doxycycline or clarithromycin may control skin eruptions. Alternative oral treatments include vitamin A medications, such as isoretinoin and antifungal medications. Unfortunately, such oral medications often cause side effects and many people have limited tolerance. Topical treatments, such as with topically applied metronidazole, isoretinoin, steroids, azelaic acid, rentinoic acid or retinaldehyde, or vitamin C preparations, are available but have limited effectiveness and cannot treat all symptoms. For example, isoretinoin has serious teratogenic side-effects and female patients of child bearing age must use effective birth control or avoid the therapy. Surgery, such as the laser elimination of blood vessels, is typically a last resort and may be prescribed if other treatments are ineffective. In patients with nose hyperplasia, surgical reduction may improve the patient's cosmetic appearance, but does not treat the disease itself. Mixed light pulse (photoderm) therapy has proved somewhat effective for symptoms associated with certain inflammatory skin orders, such as rosacea, in some patients.
Agonists of the α2 adrenoceptors have been used therapeutically for a number of conditions including hypertension, congestive heart failure, angina pectoris, spasticity, glaucoma, diarrhea, and for the suppression of opiate withdrawal symptoms (J. P. Heible and R. R. Ruffolo Therapeutic Applications of Agents Interacting with α-Adrenoceptors, p. 180-206 in Progress in Basic and Clinical Pharmacology Vol. 8, P. Lomax and E. S. Vesell Ed., Karger, 1991). Adrenoreceptor agonists, such as clonidine, have been primarily used orally, though a patch formulation is known.
Systemic side effects have been associated with the use of agonists of the α2 adrenoceptors. The side effects include, for example, cardiopulmonary effects of β-blockers like timolol; dryness of mouth, flush, fever, tachycardia, urinary retention, convulsion and irritability with atropine; hypertension with phenylephine; increased salivation, nausea, vomiting, diarrhea, stomach cramps, bronchial secretions, brionchial constriction, asthma, bradycardia, paresthesia with miotics; hypotension with clonidine; and dry mouth, fatigue and drowsiness with apraclonidine and brimonidine. See Canadian Patent No. CA2326690.
Published US Patent Application US20050276830 discloses α2 adrenergic receptor agonists and their use for treating or preventing inflammatory skin disorders.
Non-steroidal anti-inflammatory agents (NSAIDs) have been used to reduce inflammation and as analgesics. However, NSAIDS are associated with a wide spectrum of undesirable side-effects. For example, use of NSAIDs can cause direct and indirect irritation of the gastrointestinal tract (GIT), resulting in a number of adverse drug reactions (ADRs), such as nausea, dyspepsia, gastric ulceration/bleeding, and diarrhea. Risk of ulceration increases with long duration and with higher doses of NSAIDs. NSAIDs are also associated with a relatively high incidence of renal ADRs, such as salt and fluid retention and hypertension, and in rare instances, more severe renal conditions, such as interstitial nephritis, nephrotic syndrome, acute renal failure, and acute tubular necrosis. A meta-analysis of trials comparing NSAIDs found that, with the exception of naproxen, both the selective Cox-2 inhibitor and the traditional NSAID are associated with an increased cardiovascular risk (Kearney et al, BMJ 332:1302-1308 (2006)).
Accordingly, there remains a need of novel methods and compositions for ameliorating inflammatory skin disorders, such as rosacea, and their symptoms, with no or very little side effect. Such methods and compositions are described in the present application.